Asthma and atopic disease are increasingly prevalent worldwide, yet the mechanisms leading to this increase remain unknown. However, respiratory viral infections have been implicated in the development of asthma and atopy, as well as the induction of asthma exacerbations. The atopic risk has been assumed to be due to the anti-viral immune response. One of the earliest immune cell types to respond to respiratory viral infections is the polymorphonuclear neutrophil (PMN). In a mouse model utilizing Sendai virus (SeV), a paramyxovirus similar to the human Respiratory Syncytial Virus, a subset of the first responding neutrophils is found to be critical to the later development of post-viral atopic airways disease (persistent airway hyperreactivity and mucus cell metaplasia). In this model, the translation of the anti-viral response into IL-13 dependent mucus cell metaplasia is type I interferon (IFN) dependent and requires induction of the high affinity receptor for IgE (Fc?RI) on mouse lung conventional dendritic cells (cDC). A specific subset of PMN which expresses the integrin CD49d (CD49d+ PMNs), found in the bronchoalveolar lavage (BAL) during SeV infection, has been shown to be necessary and sufficient to drive Fc?RI expression on lung cDC through a cognate interaction.
The aims of this project will test the hypothesis that development of post-viral atopic disease depends upon the interaction of CD49d+ PMN with lung cDC, which is a result of specific anti-viral immune signals that lead to CD49d+ PMN development and migration from the bone marrow to the lung.
The first aim will determine the mechanisms by which CD49d+ PMN induce Fc?RI expression on cDC during SeV infection.
The second aim will determine the mechanism of the anti-viral immune response mediated development and recruitment of pro- atopic CD49d+ PMN. In addition to the proposed science, this grant includes a defined mentoring plan -- addressing competencies in research, grant-writing, communication, and laboratory management -- that will ensure the transition of the applicant from mentee to independent scientist, focusing on translational research in innate immunity and atopic diseases. Toward these goals, the applicant has obtained her institution's commitment to provide the appropriate environment with all of the necessary institutional and intellectual support, as well as the required equipment to ensure that the applicant will be able to not only successfully complete the proposed research plan, but also develop independence in the process.
The proposed studies offer important insights into a specialized group of neutrophils that links acute respiratory viral infections to the development o asthma. These studies will help pave the way for new treatment approaches to respiratory viral infections that may prevent or treat asthma.
| Cheung, Dorothy S; Sigua, Jerome A; Simpson, Pippa M et al. (2018) Cysteinyl leukotriene receptor 1 expression identifies a subset of neutrophils during the antiviral response that contributes to postviral atopic airway disease. J Allergy Clin Immunol 142:1206-1217.e5 |
